Cellular Freight Protein YKT6 Emerges as a Driver of Lung Cancer Growth

Lung cancer remains the deadliest malignancy worldwide, claiming roughly 1.8 million of the 2.2 million people diagnosed each year, and despite remarkable progress in immunotherapy and targeted drugs, the five-year overall survival rate still hovers at only about 16 percent. Against this sobering backdrop, a new study published in Holistic Integrative Oncology points to an unexpected culprit: a small trafficking protein better known for shuttling vesicles between cellular compartments than for driving tumors. The research, led by Yangbo Wei, Zhenzhen Gao and colleagues at North China University of Science and Technology under senior author Jing Chen, reports that the SNARE protein YKT6 is markedly overproduced in lung cancer tissue, where it fuels proliferation, migration and invasion while simultaneously suppressing autophagy, the cell’s self-cleaning recycling system.

YKT6 belongs to the SNARE family, a group of soluble N-ethylmaleimide-sensitive factor attachment protein receptors that mediate the fusion of membranes inside cells. What distinguishes YKT6 from most of its relatives is its unusual lipid anchor at the C-terminus, which allows the protein to flip between a closed, cytoplasmic state and an open, membrane-bound conformation, a switch regulated by lipidation and phosphorylation of the SNARE core. In its normal duties, YKT6 ferries cargo from the endoplasmic reticulum to the Golgi apparatus, helps route acidic hydrolytic enzymes to lysosomes, and, crucially, participates in the fusion of autophagosomes with lysosomes during autophagy. It has also been implicated in Wnt secretion in neurons and in the autophagic-lysosomal dysfunction seen in Parkinson’s disease, making its appearance in cancer biology both plausible and provocative.

Earlier work had already hinted that this trafficking protein could have a dark side. In breast cancer, aggressive tumor samples overexpress YKT6, which promotes leucine uptake, cell proliferation and drug resistance. In oral squamous cell carcinoma, elevated YKT6 correlates with invasion, metastasis and poor prognosis, and in hepatocellular carcinoma its expression tracks with tumor size, grade, metastasis, microvascular invasion and alpha-fetoprotein levels. Studies of non-small cell lung cancer had even linked YKT6 expression in primary tumors to macrophage PD-L1 and the glucose transporter GLUT-1. Yet, as the authors note, YKT6 had received comparatively little attention in lung cancer specifically, prompting the team to mount a combined bioinformatics and laboratory investigation of its expression, clinical relevance and mechanism of action.

The clinical arm of the study drew on large public datasets. Mining the UALCAN platform and The Cancer Genome Atlas, the researchers found that YKT6 messenger RNA is significantly elevated in lung cancer compared with normal lung tissue, and that tumor expression levels correlate with nodal metastasis status, cancer stage, TP53 mutation status and smoking history. Immunohistochemical images from the Human Protein Atlas reinforced the message at the protein level: normal lung tissue showed only faint YKT6 staining, while lung cancer specimens stained intensely. When patients were split at the median YKT6 expression value, those in the high-expression group had significantly worse overall survival and recurrence-free survival. Univariate Cox regression flagged tumor grade, T stage and N stage as prognostic indicators, and multivariate analysis confirmed T stage and tumor grade as independently significant, placing YKT6 alongside established clinical markers.

To test whether YKT6 actively drives malignant behavior rather than merely marking it, the team compared protein levels across four cell lines: the normal lung epithelial line BEAS-2B and three cancer lines, A549, H460 and H1299. Western blots showed that all three cancer lines produced far more YKT6 than the normal cells, and the two highest expressers, A549 and H460, were selected for functional experiments. Using small interfering RNA to silence YKT6, the researchers then measured cell viability by MTT assay and replicative capacity by colony formation. Both readouts dropped sharply after knockdown: cancer cells became less viable and formed fewer colonies, while the normal line was unaffected in the same way. The conclusion was straightforward. YKT6 is not a passive bystander in lung cancer; removing it directly impairs the proliferative engine of the tumor cells.

Motility assays told a parallel story. In scratch wound experiments, monolayers of YKT6-silenced cells closed their gaps far more slowly than controls, and Transwell chambers, including Matrigel-coated versions that test invasion through a basement membrane mimic, showed markedly fewer migrating and invading cells after knockdown. Because migration and invasion in carcinoma cells are typically governed by the epithelial-mesenchymal transition, or EMT, the team probed the relevant proteins by western blot. Silencing YKT6 raised levels of E-cadherin, the epithelial adhesion molecule whose loss is the hallmark of EMT, and lowered levels of Slug and Snail, the transcription factors that repress the E-cadherin promoter. In other words, YKT6 appears to hold lung cancer cells in a mobile, invasive, mesenchymal-like state, and dialing it back partially restores their epithelial restraint.

Perhaps the most intriguing finding concerns autophagy, the process by which cells engulf their own cytoplasmic contents in double-membraned autophagosomes and degrade them after fusion with lysosomes. Because YKT6 is one of the SNARE proteins required for that fusion step, the researchers used acridine orange staining, which lights up acidic autophagic vacuoles in red fluorescence, to gauge autophagic flux. Knocking down YKT6 increased the red fluorescent signal in A549 and H460 cells, and western blots confirmed the shift: the autophagy substrate p62 fell while lipidated LC3-II rose, both signatures of enhanced autophagy. The team then examined the PI3K/AKT/mTOR pathway, a classic brake on autophagy, and found that YKT6 knockdown reduced PI3K, phosphorylated AKT and phosphorylated mTOR without changing total AKT or mTOR. The data suggest that abundant YKT6 in lung cancer cells suppresses autophagy by keeping this pro-survival pathway active, even as the protein’s own fusion machinery is hijacked elsewhere in the cell.

To map YKT6’s broader regulatory landscape, the investigators turned to the LinkedOmics database, using its LinkFinder module to identify co-expressed genes across the lung cancer cohort and then running Gene Ontology and KEGG enrichment analyses. The co-expression network was dominated by genes involved in chromosome segregation, cell division, DNA replication, the mitotic cell cycle and DNA recombination, with KEGG analysis awarding its highest enrichment score to the cell cycle pathway. Flow cytometry then delivered the mechanistic payoff: silencing YKT6 reduced the proportion of cells in G1 phase and increased the proportion in S phase, producing an S-phase block. Western blots showed that Cyclin A and Cyclin D1, the cyclins that push cells through the cycle, dropped after knockdown, while the CDK inhibitors p21 and p27 rose. The pattern aligns with earlier work showing that overexpressed YKT6 modulates cell cycle progression in kidney cells, and it positions YKT6 as a genuine cell cycle regulator rather than a mere passenger.

Taken together, the study sketches a coherent model in which a conserved vesicle-trafficking protein moonlights as an oncogenic hub in lung cancer, simultaneously promoting proliferation and EMT-driven invasion, restraining autophagy through PI3K/AKT/mTOR signaling, and steering cells through the division cycle by tipping the balance of cyclins and CDK inhibitors. The authors caution that their work is built on bioinformatics and in vitro cell line experiments, so clinical validation will be needed before YKT6 can be considered a biomarker or drug target, but the therapeutic logic is appealing: tumors that depend on YKT6 for growth and spread might be vulnerable to agents that block its lipid anchoring or its SNARE-mediated fusion activity, strategies already being explored in the context of Parkinson’s disease research. For a disease that still kills four out of five of those it strikes within five years, a new handle on the machinery of malignancy is a lead worth chasing.

Subject of Research: The role of the SNARE protein YKT6 in lung cancer cell proliferation, migration, invasion and autophagy regulation

Article Title: High expression of YKT6 promotes lung cancer cell proliferation and inhibits autophagy

Article References: Wei, Y., Gao, Z., Qi, B., Wu, Y., & Chen, J. (2026). High expression of YKT6 promotes lung cancer cell proliferation and inhibits autophagy. Holistic Integrative Oncology, 5(1), Article 24. https://doi.org/10.1007/s44178-026-00240-5

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00240-5

Keywords: YKT6, lung cancer, SNARE protein, autophagy, PI3K/AKT/mTOR, EMT, cell cycle, proliferation, invasion, biomarker, TCGA, non-small cell lung cancer